A wide variety of 5-acyl-1-hydrocarbylpyrrole-2-acetic acids are known to possess useful pharmacological properties. For example, 1-methyl-5-p-toluoylpyrrole-2-acetic acid has a marked anti-inflammatory activity [J. Pharmacology and Experimental Therapeutics, 185, 127 (1973)]. See also U.S. Pat. Nos. 3,752,826; 3,755,307; 3,803,169; 3,803,171 and 4,048,191 (the disclosures of which are incorporated herein) which describe, inter alia, numerous 5-acyl-1-hydrocarbylpyrrole-2-acetic acids having anti-inflammatory and analgetic activities.
In copending application Ser. No. 963,673, filed Nov. 27, 1978 (the disclosure of which is incorporated herein), Kondo, Suda and Tunemoto describe a novel and useful process for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid. In that process, a 5-cyano-1-hydrocarbylpyrrole-2-acetic acid is reacted with a Grignard compound and then the resultant reaction product is hydrolyzed. The use of solvents is preferred and examples of the solvent used in the Kondo et al. acylation process are ethers such as ether, dioxane, tetrahydrofuran, dimethoxyethane and the like or hydrocarbons containing organic tertiary amines. A Grignard reagent is prepared in these solvents and then the 5-cyano-1-hydrocarbylpyrrole-2-acetic acid is added. The reaction can preferably be carried out at room temperature or at a reflux temperature of the solvent used. Preferably, the Grignard reagent is used in an amount of more than two molar equivalents. One molar equivalent of Grignard reagent is consumed for the production of carboxylic acid salt and the balance is used for the introduction of the acyl group.
The reaction mixture formed in the Kondo et al. acylation process is worked up and then hydrolyzed. The hydrolysis can be accomplished by the direct addition of acidic substances such as hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, aqueous ammonium chloride and the like. From the standpoint of the reaction mechanism, the reaction is deemed to proceed via the formation of a ketimine salt as an intermediate.
Although the foregoing process of Kondo et al. is a significant contribution to the art, it nonetheless is not without its shortcomings. In particular, to achieve optimum yields, relatively long reaction periods have been used. In practical short reaction times the reaction was found to have occurred only to a limited extent--a substantial amount of unreacted cyano acid starting material was recoverable from the reaction mixture even though the reaction system contained a substantial excess of the Grignard reagent. For instance, in their Example 8, 1-methyl-5-p-toluoylpyrrole-2-acetic acid was produced in a yield of about 63.5% based on the 5-cyano-1-methylpyrrole-2-acetic acid reactant employed, after a reaction period at reflux of two hours. On the other hand, in their Example 9 this product was formed in an 84% yield based on the initial cyano acid, but in this case, a 21-hour reflux reaction period was involved. Obviously, long reaction periods such as this severely curtail productivity and add significantly to plant and operating costs.